Heat shock proteins (Hsp's) play a key role in cell protection against various cell stress factors (i.e. toxic xenobiotic, chemotherapy, radiation) acting as a protective factor against the misfolding of essential proteins involved in maintaining cell functionality. Hsp90 proteins, members of these molecular chaperones are proteins that play a key role in the conformational maturation, stability and function of so-called “client” proteins, many of them belonging to the oncogenic protein family, such as Bcr-Abl, p53, Raf-1, Akt/, ErbB2, EGFR, Hif and other proteins, as well as steroid hormone receptors. The inhibition of Hsp90 triggers the disruption of the Hsp90-client protein complex, and subsequently, its proteasome-mediated degradation causes loss of function and inhibition of cell growth. Interestingly, heat shock protein 90 has emerged as an important target in several diseases. In particular, the role played by Hsp90 in regulating and maintaining the transformed phenotype in cancers and neurodegenerative diseases has been recently identified, as well as its roles in fungal and viral infections (Solit D. B., et al., Drug Discov. Today, 2008, 13(1-2), 38). In particular, Hsp90 inhibition has also been reported to be beneficial in the treatment of neurodegenerative diseases such as dementia with Lewy bodies, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, spinocerebellar ataxias, Parkinson, Huntington and Alzheimer's diseases (Taylor D. M., et al., Cell Stress Chaperones, 2007, 12, 2, 151; Yang Z., et al., Nat. Med., 2007, 13, 3, 348; Katsuno M., et al., Proc. Natl. Acad. Sci. USA, 2005, 12, 46, 16801; Gallo K. A., Chem. Biol., 2006, 13, 115; Luo W., et al., Proc. Natl. Acad. Sci., 2007, 104, 9511; Macario A. J., et al., N. Engl. J. Med., 2005, 353, 1489; Dou F., et al., Int. J. Mol. Sci., 2007, 8, 51); inflammatory diseases (Vega V. L., et al., Mol. Biol. Cell., 2003, 14, 764; Poulaki V., et al., Faseb J., 2007, 21, 2113); cerebral ischemia (Lu A., et al., J. Neurochem., 2002, 81, 2, 355) and malaria (Kumar R., et al., J. Biosci., 2007, 32, 3, 531).
Moreover, many Hsp90 client proteins are over-expressed in cancer, often in mutated forms, and are responsible for unrestricted cancer cell proliferation and survival. Interestingly, Hsp90 derived from tumour cells has particularly high ATPase activity with higher binding affinity to Hsp90 inhibitors than the latent form in normal cells, allowing specific targeting of Hsp90 inhibitors to tumour cells with little inhibition of Hsp90 function in normal cells (Chiosis G., et al., ACS Chem. Biol., 2006, 1, 5, 279). In addition, Hsp90 has also been recently identified as an important extracellular mediator for tumour invasion (Eustace B. K., et al., Nature Cell Biol., 2004, 6, 6, 507; Koga F., et al., Cell cycle, 2007, 6, 1393).
Thus, Hsp90 is considered a major therapeutic target for anticancer drug development because inhibition of a single target represents attack on all of the hallmark traits of cancer.
Since the discovery that two natural compounds, geldanamycin and radicicol, were able to inhibit Hsp90 function through binding to an ATP binding pocket in its N-terminal domain, the interest for Hsp90 inhibitors has grown. The natural antibiotic geldanamycin was shown to exhibit potent antitumour activity against human cancer cells (Whitesell L., et al., Cancer Res., 1992, 52, 1721), but significant toxicity prevented its clinical development (Supko J. G., et al., Cancer Chemother. Pharmacol., 1995, 36, 305).
The first-in-class Hsp90 inhibitor to enter clinical trials was the geldanamycin analogue 17-AAG (17-allylaminogeldanamycin). Even though high in vitro activity characterizes this geldanamycin derivative, its interest is shadowed by poor solubility coupled to hepatotoxicity properties. Some of these problems have been partially solved by the discovery of 17-dimethylaminoethylgeldanamycin.
Radicicol, a natural macrocyclic anti-fungal antibiotic, was found to inhibit Hsp90 protein by interacting at a different site of action than Geldanamycin (Sharma S. V., et al., Oncogene, 1998, 16, 2639). However, due to its intrinsic chemical instability it was deprived of in vivo activity.
Another important class of inhibitors resides in the purine scaffold. This class of derivatives was devised by structural homology with ATP. Among the many inhibitors developed within this family, PU24FCl was found to possess high in vitro and in vivo activity (He H., et al., J. Med. Chem., 2006, 49, 381).
High-throughput screening campaigns permitted the discovery of benzisoxazole derivatives endowed of Hsp90 inhibitory properties having a resorcinol moiety in position 3 (Gopalsamy A., et al., J. Med. Chem., 2008, 51, 373).
Among the different class of Hsp90 inhibitors, Vernalis Ltd. has disclosed 4,5-diarylpyrazoles (Cheung K. M., et al., Bioorg. Med. Chem. Lett., 2005, 15, 3338); 3-aryl,4-carboxamide pyrazoles (Brough P. A., et al, Bioorg. Med. Chem. Lett., 2005, 15, 5197), 4,5-diarylisoxazoles (Brough P. A., et al., J. Med. Chem., 2008, 51, 196), 3,4-diaryl pyrazole resorcinol derivative (Dymock B. W., et al., J. Med. Chem., 2005, 48, 4212; Smith N. F., et al., Mol. Cancer Ther., 2006, 5, 6, 1628) and thieno[2,3-d]pyrimidine (WO2005034950, AACR 2009, Denver, Colo., poster 4684).
WO2003013517 reports 3-aryl-5-aminoisoxazole derivatives as kinase inhibitors useful as anticancer agents.
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However, to date, no Hsp90 inhibitors fully satisfy the requisites of safety and stability. Therefore, the desire of potent and selective Hsp90 inhibitors remains an interesting and promising goal. We have now found that 4-amino substituted aryl isoxazole are endowed of high and unexpected Hsp90 inhibitory properties.